Safety and Pharmacokinetics Study of Oral Lithium in Patients With Chronic Spinal Cord Injury

A Three Month, Open-label, Single-arm Trial Evaluating the Safety and Pharmacokinetics of Oral Lithium in Patients Diagnosed With Chronic Spinal Cord Injury

The current study is a phase I open-label clinical trial to examine plasma levels after oral lithium treatments in 20 subjects with chronic spinal cord injury. The subjects will receive standard doses of oral lithium used in treatment of manic depression. The goal of the trial is to show feasibility and safety of maintaining plasma levels of 0.6 mmol/L to 1.2 mmol/L for six weeks in subjects with chronic spinal cord injury.

Patients with spinal cord injury (SCI) usually have permanent and often devastating neurological deficits and disability. There has been successful research in a number of fields that may someday help people with spinal cord injuries.

The planned treatment trials will focus on the effects of oral lithium on neurological function in people with chronic spinal cord injury and those that have received umbilical cord blood mononuclear cell transplants to the spinal cord. The interest in these two treatments derives from recent reports indicating that umbilical cord blood stem cells may be beneficial for spinal cord injury and that lithium may promote regeneration and recovery of function after spinal cord injury. Both lithium and umbilical cord blood are widely available therapies that have long been used to treat diseases in humans.

The current study is a phase I open-label clinical trial to examine plasma levels after oral lithium treatments in 20 subjects with chronic spinal cord injury. The subjects will receive standard doses of oral lithium used in treatment of manic depression. The goal of the trial is to show feasibility and safety of maintaining plasma levels of 0.6 mmol/L to 1.2 mmol/L for six weeks in subjects with chronic spinal cord injury.

Lithium attracted much attention as a potential neuroregenerative therapy based on experiments in animal models of SCI in 2004. However, toxic levels of lithium (>1.5 mmol/L) are close to the effective levels (0.6 - 1.2 mmol/L). At toxic levels, patients may become confused and lethargic, have diarrhea, upset stomach, and develop tremors, ataxia, dysarthria, and nystagmus. Lithium toxicity may be compounded by sodium depletion or diuretics (thiazides) that inhibit kidney sodium upgrade and ACE inhibitors. Plasma levels also depend on fluid input/output. Therefore, care will be taken to titrate the dose and to test plasma levels of the drug at the beginning, at day 2, 7, and week 6 during the treatment period.

Acute toxicity usually produces relatively mild symptoms. Chronic lithium toxicity may lead to more severe neurotoxic symptoms. However, these symptoms usually develop after 3-5 years of treatment.

Data obtained from this study will be used to develop future chronic spinal cord injury clinical studies: (1) randomized controlled trials with lithium versus placebo; and (2) randomized controlled trials comparing effects of lithium and placebo on subjects who have received umbilical cord blood mononuclear cell transplants to the spinal cord.

Inclusion Criteria:

• Subjects of either gender and 18 - 60 years of age (preferably 10 males and females each)
• Subjects with chronic spinal cord injury (defined as 12 months or more post spinal cord injury), as confirmed by a MRI
• Subjects with neurological status: ASIA A, B or C
• Subjects must be able to read, understand, and complete the VAS
• Subjects who have voluntarily signed* and dated* an informed consent form, approved by an IEC/IRB, prior to any study-specific procedures *If a subject consents to participation but is not in a position to personally sign and date the informed consent form because of his or her physical condition, the consent must be confirmed at the time of consent orally, signed on behalf by the subject's relative, and by an impartial witness who is present throughout the whole informed consent process.

Exclusion Criteria: Subjects are excluded if they have

• a history of hypersensitivity to lithium
• significant renal, cardiovascular, hepatic and psychiatric diseases
• significant medical diseases or infection
• brain injury
• Addison's disease
• debilitation or dehydration
• recently taken or are taking diuretics or other drugs with known interaction with lithium, such as tricyclic antidepressants, NSAIDs and tetracycline
• a history of alcohol abuse or drug abuse, or if they are
• pregnant or lactating women;
• female of childbearing potential and are unwilling to use an effective contraceptive method while enrolled in the study;
• subjects who are currently participating in another investigational study or have been taking any investigational drug within the last 4 weeks prior to screening of this study (Visit 1); and finally,
• any criteria, which, in the opinion of the investigator, suggest that the subject would not be compliant with the study protocol.